TRED-HF - Withdrawal of HF meds in patients with recovered (non-ischemic) dilated cardiomyopathy
Bottom Line: In patients with recovered dilated cardiomyopathy (DCM), even careful withdrawal of HF medications will result in relapse of DCM (based on clinical signs, imaging or biomarkers) in approximately 4 out of 10 patients within 6 months, compared to no deterioration in this timeframe if these medications are continued.
These medications should be considered “lifelong” medications until we have tools that can reliably predict which patients can stop them without deteriorating.
Context
In patients who initially have HF with reduced ejection fraction (HFrEF), recovery of ejection fraction >50% portends a more favorable prognosis
e.g. In one study, vs patients who had initial HFrEF followed by LVEF recovery to >50%, patients with non-recovered HFrEF had an increased risk of death, transplant or VAD placement (HR 3.4) & CV hospitalization (HR 1.8)
The 2017 Canadian Cardiovascular Society (CCS) heart failure (HF) guidelines recommend consideration of monitored, sequential discontinuation of HF meds in certain subsets of patients with recovered non-ischemic cardiomyopathy
Including: chemotherapy-related, ETOH overuse-related, peripartum, tachycardia-related, or valvular cardiomyopathy
If: Asymptomatic (NYHA 1), LVEF and LV volumes normalized, trigger eliminated (e.g. ETOH abstinence, HR controlled, valve repaired/replaced)
There is limited evidence for pharmacological treatment withdrawal in patients with HFrEF who get EF recovery
e.g. in an early observational study of 13 participants with DCM taking metoprolol for >2.5 years who weaned off metoprolol, 54% (7/13) experienced clinical deterioration (4 deaths & 3 patients who worsened by 1 NYHA functional class).
Design: Open-label RCT (pilot trial designed to plan larger trial)
Patients (n=51)
Included if:
16+ y/o
Previous dx of dilated cardiomyopathy (DCM) with LVEF 40% or lower
Currently:
NYHA functional class 1 (no current HF symptoms)
LVEF 50% or higher & left ventricular end diastolic volume indexed (LVEDVi) WNL (based on cardiac MRI, or 3D echo if MRI contraindicated)
NT-proBNP <250 ng/L
Treatment with 1+ of the following HF meds: Loop diuretic, ACEI, ARB, mineralocorticoid-receptor antagonist (MRA; spironolactone or eplerenone)
Key exclusion criteria
Uncontrolled HTN (>160/100 mmHg in clinic)
Mod-severe valvular disease
Angina
Beta-blocker required for AF/flutter, VT, or SVT
GFR <30
Pregnant.
Baseline characteristics (average of both groups unless specified)
Median age 55 y/o (IQR 45-64), male (67%)
Time since dx (4.9 y), median LVEF at dx 25%
Cause: Idiopathic (69%), familial (14%), trigger (excess ETOH, pregnancy, anthracycline, hyperthyroidism or myocarditis; 18%), pathogenic TTN truncation (22%)
Time since LVEF >50% (2 y)
CV symptom burden (0=none, 185=severe): 10-11
Quality of life using Kansas City Cardiomyopathy Questionnaire (KCCQ; 0=worst, 100=best)): 94-97
LVEF 60%, LVEDVi 83 mL/m^2, NT-proBNP 72 ng/L
Global longitudinal strain median 14% (values <16% considered abnormal)
Meds: ACEI/ARB (100%), beta-blocker (88%), MRA (47%), loop diuretic (12%)
Intervention & Comparator
Intervention: Sequential discontinuation of HF meds over max 4 months, total 6 months follow-up
Order of drug dose reduction/discontinuation:
(1) Loop diuretic (reduced by 50% q2 weeks until furosemide 40 mg/d-equivalent, then D/Ced)
(2) MRA (reduced by 50% until equivalent to spiro 50 mg/d, then D/Ced)
(3) Beta-blocker (reduced by 50% until 25% target dose or lower, then D/Ced)
(4) ACEI/ARB (reduced by 50% until 25% target dose or lower, then D/Ced)
Follow-up schedule:
Baseline: Clinic visit, symptom & QoL questionnaire, exercise stress test, cardiac MRI, NT-proBNP
q4 weeks: Clinic visit & NT-proBNP
@ week 16: Repeat cardiac MRI
@ month 6: Same as baseline
Comparator:
Phase 1 (randomized phase) x6 months: Continued all HF meds per baseline
@ baseline & month 6: Same as intervention group
@ weeks 8 & 16: Clinic visit, NT-proBNP
Phase 2: Then, non-randomized crossover to sequential discontinuation of HF meds as per intervention protocol
Results
Primary outcome: DCM relapse in 6-month randomized phase
Defined as meeting 1+ of:
Clinical HF based on signs & symptoms
LVEF reduced by >10%, to <50%
LVEDVi increased by >10%, to above normal range
NT-proBNP doubled, to >400 ng/L
Discontinuation group 44%, control group 0% (p=0.0001) - “number needed to harm” = 3 (rounded up from 2.3)
Figure 3 from TRED-HF. Kaplan-Meier curve of time to relapsed DCM comparing discontinuation versus continuation of HF meds
Secondary outcomes:
Composite safety outcome (CV death, major adverse CV events, unplanned CV hospitalization): 0 in both groups
(Select) differences in means between groups from baseline to month 6:
KCCQ: -5.1 (95% CI -9.9 to -0.4; lower with discontinuation vs continuation of HF meds)
LVEF -9.5% (lower with discontinuation vs continuation)
LVEDVi +4.7 mL/m^2 (95% CI -1.5 to +11.0, p=0.14)
Vitals: HR +15 bpm, BP +7/+7 mmHg
Inconclusive: CV symptom burden, exercise time, peak VO2, log-transformed NT-proBNP
Secondary analyses including withdrawals from phase 1 + phase 2
DCM relapse in control group phase 2: 36%
Overall DCM relapse rate after HF med discontinuation: 40% (26% relapse <2 months of discontinuation)
Figure 4 from TRED-HF. Venn diagram breakdown of component of primary outcome met (includes all withdrawals from randomized phase + single-arm crossover phase)
Internal validity
Allocation bias: Low risk
Computer-generated random sequence, 1:1 allocation in permuted blocks, stratified by baseline NT-proBNP
Centralized allocation via online system
Performance bias: Low/unclear risk
Patients & their clinicians aware of treatment allocation; however, the study employed a standardized protocol to wean & D/C HF meds, as well as standardized monitoring
Detection bias
Low risk of bias for objective outcomes (core lab MDs reading imaging unaware of study group allocation)
High risk of bias for QoL outcomes (patients completed the questionnaires aware of treatment allocation)
Attrition bias: Low risk
Loss to follow-up 2% (1 participant in withdrawal group left trial after 7 days)
Analyzed intention-to-treat population
Other Considerations
We can’t yet predict which stable, recovered DCM patients will deteriorate with D/C of HF meds
In this trial, predictors of DCM relapse after withdrawal of therapy included: greater age, use of >2 meds, use of MRA, higher NT-proBNP, lower global radial strain on cardiac MRI, & possibly lower peak VO2
However, based on univariable analysis only (no adjusting for other variables) & small n of events
DCM etiology did not clearly predict risk of deterioration with therapy withdrawal. Some patients with a seemingly reversible cause of DCM (e.g. ETOH use, pregnancy) did have DCM relapse upon D/Cing HF meds. Therefore, presence of a trigger does not indicate that D/Cing HF meds after HF remission will be safe.